The TCR is an allosterically regulated macromolecular machinery changing its conformation while working

Abstract

The αβ T‐cell receptor (TCR) is a multiprotein complex controlling the activation of T cells. Although the structure of the complete TCR is not known, cumulative evidence supports that the TCR cycles between different conformational states that are promoted either by thermal motion or by force. These structural transitions determine whether the TCR engages intracellular effectors or not, regulating TCR phosphorylation and signaling. As for other membrane receptors, ligand binding selects and stabilizes the TCR in active conformations, and/or switches the TCR to activating states that were not visited before ligand engagement. Here we review the main models of TCR allostery, that is, ligand binding at TCRαβ changes the structure at CD3 and ζ. (a) The ITAM and proline‐rich sequence exposure model, in which the TCR's cytoplasmic tails shield each other and ligand binding exposes them for phosphorylation. (b) The membrane‐ITAM model, in which the CD3ε and ζ tails are sequestered inside the membrane and again ligand binding exposes them. (c) The mechanosensor model in which ligand binding exerts force on the TCR, inducing structural changes that allow signaling. Since these models are complementary rather than competing, we propose a unified model that aims to incorporate all existing data.

Atomic-resolution view of complete TCR-CD3 revealed

“…A possible scenario might be that ligand induces transient reorientation of the TCR α/β relative to its associated CD3 subunits in their TM helices, thus enabling changes in the intracellular tails of CD3 for phosphorylation. This would agree with the notion that the TCR-CD3 complex cycles between different conformations during action (Schamel et al, 2019). Capturing of such changes, however, may not be easily amenable to structural approaches due to their transient nature.…”

“…The assembly of the TM segment of the TCR-CD3 complex can be compared to piston (formed by the two TM helices of TCRα/β) in cylinder (formed by the six TM helices of CD3). This seemingly agrees with the mechanical force-based models on TCR triggering (Schamel et al, 2019;Ma et al, 2007). However, piston-like movement of the two TM helices as proposed in the mechanosensor models would result in disruption of the functionally important ionic interactions formed within the TM segment of the complex (Call et al, 2002).…”

“…Numerous studies support conformational changes in the ECDs, TMs and the intracellular tails of TCR-CD3 during activation (Schamel et al, 2019). Then how does the cryo-EM structure fit with these data?…”

“…Several models hypothesize that pMHC or antibody binding to TCR α/β allosterically induces conformational changes in the CD3 subunits, thus exposing their intracellular signaling tails for phosphorylation by the Lck kinase and initiating signaling (Schamel et al, 2019). Unexpectedly, however, structural comparison indicated that pMHC binding induces no substantial conformational changes in the TCR-CD3 complex (Fig.…”

Mechanotransduction in T Cell Development, Differentiation and Function

“…A major group of TCR triggering models involves conformational changes. Whereas extensive crystallographic studies have not revealed sufficient amount of conformational changes in the ectodomains of the TCR-pMHC complex [90,91], convincing evidence indicates the occurrence of conformational changes in the CD3 cytoplasmic tails, which are released from the inner leaflet of the plasma membrane accompanying TCR triggering [97,98]. Force-induced conformational change has been suggested as a mechanism TCR triggering [99,100], e.g., by inducing apposition of the CD3ζζ subunits that are spread before TCR-pMHC binding [101] and/or segmenting the bipartite helix in the transmembrane domain of the TCR α-subunit to alter its association with the CD3 subunits [102], which may dislodge the CD3 tails from the plasma membrane.…”